Derivatives of benzothiadiazine-1, 1-dioxide



United States Patent 3,078,270 DERIVATIVES F BENZOTHIADIAZINE- LI-DIOXIDE Warren J. Close and Leo R. Swett, Waukegan, Ill., assignors to Abbott Laboratories, North Chicago, 111., a corporation of Illinois No Drawing. Filed Aug. 14, 1959,'Ser. No. 833,682 11 Claims. (Cl. 260-243) This invention relates to compounds cor-responding to the formula \GH-R l' I-R sand a method for their preparation. In the above formula, X represents chlorine, bromine or trifluoromethyl, R represents hydrogen or loweralkyl and R HaNOzS- $H-COOH NR OH-OOOR N--R S02 H NO IS In the above series of reactions, R, R" and R represent hydrogen or loweralkyl, R represents loweralkyl and X represents chlorine, bromine or trifluoromethyl.

Step A of the method can'be conveniently carried out by heating equimolar amounts of the sulfonamide and glyoxylic acid (preferably analkali metal salt of the acid) in water at or about the boiling temperature and under reflux until the reaction is complete. Upon cooling and acidifying, the desired 3-carboxy-6-halo-7-sulfamyl-3,4- dihydro-1,2,4-benzothiadiazine-1,l-dioxide separates as a crystalline solid which is removed by filtration and recrystallized from water or alcohol.

In step B of the method, the product obtained in Step A is esterified with a lower alkanol'such as methanol,

ethanol,'propanol or butanol in the presence of a catalyst; such as hydrogen chloride. The reaction is performed by employing a substantial molar excess of the alkanol and heating the reaction mixture preferably at or about the reflux temperature. while gassing wtih a catalyst such as hydrogen chloride. Upon completion of the reaction, the reactionniixture is cooled to precipitate the desired 3 carboalkoxy 6-halo-2-alkyl-7-sulfamyl-3,4-djhydro- 1,2,4-benzothiadiazine-l,l-tdioxide which is filtered ofi and, if desired, purified by recrystallization from a suitable -solvent; Alternatively, the excess solvent may be evaporated when the reaction is complete and the residue recrystallized to obtain the desired product.

The final step of the method is readily carried out by adding an excess of ammonia or a lower alkylamine to the product obtained in Step B. The reaction is preferably carried out at or about the boiling temperature of the amine. When the reaction is complete, the excess ammonia or amine is evaporated and the residue recrystallized from water or aqueous alcohol to obtain the desired 3-alkylcarbamyl-6-halo-2-alkyl-7-sulfamyl-3,4-dihydro-l,2,4 benzothiadiazine-1,l-dioxide as a crystalline solid.

In an alternative method of preparation ,the compounds having the formula are readily prepared by adding one molecular proportion of diazomethane dissolved in a suitable solvent such as ether to one molecular proportion of a 3-carboxy-6-halo- 7 sulfamyl 3,4-dihydro-l,2,4-benzothiadiazine-l,l dioxide dissolved in a suitable solvent such as methanol; The reaction takes place smoothly at room temperature; When the reaction is complete, the solvents are evapo rated and the residue recrystallized from methanol or other suitable solvents to obtain the desired product.

The compounds of the present invention which correspond to the formula may be prepared, if desired, by the reaction of one molecular proportion of a 3-carboxy-6-ha'lo-7-sulfamyl-3,4-di hydro-l,2,4-benzothiadiazine-l,l-dioxide with" two molec ular proportions of an alkylating agent such as diazomethane in-the same manner as that describedwhen only one molecular proportion of diazomethane isemployed.

The following examples illustrate the invention but are not to be construed as a limitation thereof.

EXAMPLE 3-Carb0xy-6-Chl0r0-7-Sulfamyl-3,4-Dihydro-I ,2,4- Bnzothiadiazine-I ,1 -Di0xide 5 on-o OOH 112N023 /NH Asu'spension of 22.8 grams (.08 mole) of 4 ami'no-6- chlloro-1,3-benzenedisulfonamide in 300 ml. of water was heated at the boiling temperature and under reflux. Thereafter, 8.8 grams (.12 mole) of glyoxylic acid dis solved in one equivalent of 5% aqueous sodium hydroxide was added portionwise with stirring and the resulting mixture refluxed for 1.5 hours. Upon" completion of the reaction, the reaction mixture was'coole'd and aciditied to precipitate awhite solid. After recrystallization of this solid from water, the desired 3-carboxy-6-chloro-7- sulfamyl 3,4dihydro-l,2,4-benzothiadiazine-1,1-dioxide compound was obtained as a hydrate which melted at 125 C. with decomposition. Anal.--Calcd. for

C8H8CIN3OGSZ C=25.4%; H=3.2%. Found: C=25.4%, H=3.2%.

EXAMPLE 2 3-Carbamoethoxy-6-Chl0r0-7-Sulfamyl-3,4-Dihydr0- 1,2,4-Benzthiadiazine-I ,1 -Di0xide To a solution of 1.71 grams (.005 mole) of 3-carboxy- 6 chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine- 1,1-dioxide in 10 m1. of methanol was added portionwise with stirring at room temperature, .21 gram (.005 mole) of diazomethane dissolved in 40 ml. of ether. The solvents were thereafter evaporated and the residue recrystallized from methanol to obtain the above-named product as a crystalline solid melting at 234-236 C. Anal.Calcd. for C H ClN O S C=30.4%; H=2.8%. Found: C=30.4%; H=3.0%.

EXAMPLE 3 3-Carbom ethoxy-6-Clzl0ro-2-Methyl-7-Sulfamyl-3,4-

Dihydro-1,2,4-Benzothiadiazine-1,1-Dioxide f? it CH'C-OCH3 N-CH; H.NO2S

This compound was prepared in the same manner as that described in Example 2 except that the amount of diazomethane employed was doubled. The compound was found to melt at 224225 C. Anal.--Calcd. for C H CIN O S C=32.5%; H=3.2%. Found: C=32.6%; H=3.5%.

In an alternative method of preparation, 20 grams (.053 mole) of 3carb0xy-6-chloro-2-methyl-7-sulfamyl- 3,4 dihydro-l,2,4-benzothiadiazine-l,l-dioxide monohydrate (M.P.=154 C.) was dissolved in 100 m1. of methanol to which was added 6 grams of acetone dimethyl acetal and 2 ml. of concentrated hydrochloric acid. Thereafter, two more G-gram portions of the acetal were added at room temperature at one hour intervals. The resulting mixture was heated overnight at 50 C. The solvents were then removed under reduced pressure and the residue recrystallized from a methanol-water mixture to obtain the desired 3-carbomethoxy-6-chloro-2-methyl-7- sulfamyl 3,4-dihydro1,2,4-benzothiadiazine-1,1-dioxide which melted at 225 C.

EXAMPLE 4 3-Carb0xy-6-Chlore-2-Methyl-7-Sulfamyl-3,4-Dihydro- 1,2,4-Benz0thiadiazine-1 ,1 -Di0xide Six grams (.02 mole) of 4-amino-6-chloro-3-(methylsulfamyl)-benzenesulfonamide were dissolved in 60 ml. of water and the resulting solution heated at the boiling temperature and under reflux. A solution of 2.2 grams (.03 mole) of glyoxylic acid in ml. of water was then added and the reaction mixture heated at the boiling temperature and under reflux for one hour. The reaction mixture was thereafter cooled to precipitate the desired above-named product as a hydrate which was separated by filtration. M.P.=156-157 C. AnaL-Calc'd. for

EXAMPLE 5 3-Carbamy [-6 -Ch loro-Z-M ethyl-7-Szzl fam yl-3,4-Dilz ydro- Found:

1 ,2,4-Benzotlziadiazine-l ,1 -Dioxide 3 Ii on-c-Nm nmms To 100 ml. of liquid ammonia at room temperature was added 2.9 grams (.0078 mole) of the product prepared in Example 3. The excess ammonia was thereafter evaporated and ml. of water added to the residue. The white solid which precipitated was separated by filtration and found to melt at 245247 C. Upon analysis, the

nitrogen content of 15.8% was found to agree with the calculated value for 3-carbamyl-6-chloro-2-methyl-7-sulamyl-3,4-dihydro-1,2,4-benzothiadiazine-l,l-dioxidc.

EXAMPLE 6 6-Chl0ro-3-(Dimethylcarbamyl)-2-Z'rdethyl-7-Sulfamyl- 3,4-Dihydr0-1 ,2,4-Benzoth iadiazirze-J ,1 -Di0xia'e This compound was prepared by adding 7.12 grams (.02 mole) of 3-carbomethoxy-6-chloro-2-methyl-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1 dioxide to ml. of dimethylamine at room temperature. The excess amine was then evaporated and 25 ml. of water added to the residue. The desired product precipitated as a white solid and after recrystallization from a methanolwater mixture melted at 265-267 C. with decomposiilOIl. Anal.Calcd. fOl' C11H15CHI4O5SQI H=3.9%. Found: C=34.6%; H=4.2%.

EXAMPLE 7 3-( n-Buzylcarbamyl) -6-Chl0r0-2-Methyl-7-Sulfamyl- 3,4-Dilzydr0-1,2,4-Benz0rhiadiazine-1,I-Dioxia'e This compound was prepared by the reaction of 1.0 gram (.0027 mole) of 3-carbomethoxy-6-chloro-2-methyl- 7 sulfamyl 3,4 dihydro 1,2,4 benzothiadiazine 1,1- dioxide with 10 ml. of n-butylamine in a manner similar to that described in Example 6. The resulting product was a white solid which melted at 260 C.

EXAMPLE 8 6-Brom0-3-Carboxy-Z-Methyl-7-Sulfamyl-3,4-Dihydr0- 1,2,4-Benzothiadiazine-I,1-Dioxide e on-oo or:

HzNOzS- N CH3 EXAMPLE 9 6 -Brm0-3 -Carbometh0xy-2-M ezhyl-7-Sulfamyl-3,4- Dihydro-I ,2,4-Benz0thiadiazine-J ,1 -Dioxide' EXAMPLE l0 3-Carboxy-7-SuZfamyl-6-Trifluoromrthyl-3,4-Dihydror- 1 ,2,4-Benzothiadiazine-1 ,1 -Di0xia'e To arefiuxing solution of 1.0 gram (.003 mole) of 4-amino-6-trifiuorornethyl-l,3-benzenedisulfonamide in 15 ml. of water was added a solution of 0.33 gram (.0045 mole) of glyoxylic acid in ml. of water. Following the addition, the reaction mixture was refluxed for 1.5 hours. Upon cooling, the desired product precipitated and was separated by filtration. IvI.P.=220 C. with decomposition.

EXAMPLE 11 3-Carb0xy-6Chl0r0-2-Ethyl-7-Sulfamyl-3,4-Dihydr0- 1 ,2,4-Benz0thiadiazine-1 ,1 -Di0xide This compound was prepared in the same manner as that described in Example 4 by the reaction of 4-amino 6chloro-3-(ethylsulfamyl) benzenesulfonamide (ll/LR: 152-154 C.) and glyoxylic acid. The monohydrate was a white solid which melted at 190191 C. with decomposition. Upon analysis, the product was found to contain 30.98% C; 3.92% H and 11.07% N compared to the theoretical values of 30.96% C; 3.63% H and 10.83% N.

EXAMPLE 12 3-Carb0methoxy-6-Chloro 2-Ethyl-7-Sulfamyl-3,4-DihydroJ ,2 ,4 -B enzoth iadiazine-J ,1 -Di0xide This compound was prepared by the reaction of the compound prepared in Example 11 with excess methanol. The procedure was identical to that described in the alternative method employed in Example 3. The product was a crystalline solid which melted at 222-224 C.

EXAMPLE 13 6 -Ch loro-Z-M ethyl-3- (M ethy lcarbamyl -7-S ulfamyl-S ,4-

6 This compound was prepared by adding .02 mole of 3-carbomethoxy 6 chloro-2-methyl-7-sulfamyl-3,4-dihydro-l,2,4-benzothiadiazine-1,1-dioxide to ml. of monomethylamine at room temperature. The excess amine was thereafter evaporated and the residue crystallized from a methanol-water mixture to obtain the desired.

product as a white, crystalline solid melting at 270271 C. with decomposition. The product was further identi- By the reaction of 4-amino-6-chloro3-(isopropyl-sulfamyD-benzenesulfonamide (M.P.=15Sl57 C.) with gly'oxylic acid as described in Example 4, the desired 3- carboxy-6-chloro-2-isopropyl-7-sulfamyl 3,4 dihydro 1,2,4-benzothiadiazine-1,1-dioxide is obtained. Further reaction with excess methanol as described in the alternative method employed in Example 3 results in the formation of 3-carbomethoxy-6-chloro-2-isopropyl-7-sulfamyl- 3,4 dihydro-1,2,4-benzothiadiazine-l,l-dioxide.

In a manner similar to that described in the foregoing; examples, other derivatives of 7-sulfamyl-3,4-dihydro- '1,2,4-benzothiadiazine-1,l-dioxide can be prepared of which the following are representative:

3-carboxy-6-chloro-2-n-butyl derivative by the reaction of 4-amino-6-chloro-3-(n-butylsulfamyl) benzenesulfonamide with glyoxylic acid. Further reaction of this derivative with methanol, ethanol, n-propyl alcohol or tert. butyl alcohol in the presence of hydrogen chloride results in the formation of the 3-carbomethoxy-6-chloro-2-nbutyl;' 3-carbethoxy-6chloro-2-n-butyl; 3-carbo-n-propoxy-6-chloro-2-n-butyl and 3-carbo-tert.-butoxy-6-chloro- Z-n-butyl derivatives, respectively. Subsequent reaction of any of these 3-carboalkoxy-6-chloro-2-n-butyl derivatives with ammonia, monomethylamine, dimethylamine, monoethylamine, diethylamine, monopropylamine, dipropylamine, monobutylamine or dibutylamine will produce the 3-carbarnyl 6 chloro-2-n-butyl; 3-methylcarbamyl-6- chloro-Z-n-butyl; 3-dimethylcarbamyl-6-chloro-2-n-butyl; 3-ethylcarbamyl-6-chloro-2-n-butyl; S-diethylcarbamyl-G- chloro-Z-n-butyl; 3-propylcarbamyl-6-chloro-2-n-butyl; 3F dipropylcarbamyl-6-chloro-2-n-butyl; 3-butylcarbamyl 6 chloro-Z-n-butyl and 3-di'butylcarbamyl-6'chloro-2-n-buty1 derivatives of 7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-Ll-dioxide, respectively.

3-carboxy-6-bromo-2-ethyl derivative by the reaction of 4-arnino-6-bromo-3(ethylsulfamyl) benzenesulfonamide with glyoxylic acid. Further reaction of this derivative with methanol, ethanol, isopropyl alcohol or sec. butyl alcohol in the presence of hydrogen chloride results in the formation of the 3-carbomethoxy-6-bromo-2-ethyl; 3'- carbethoxy-6-bromo-2-cthyl; 3-carbo-isopropoxy-6-bromo- 2-ethyl and 3-carbo-sec.-butoxy-6-bromo-2-ethyl derivatives, respectively. Subsequent reaction of any of these 3 carboalkoxy-6-brorno-2-ethyl derivatives with ammonia, monomethylamine, dimethylamine, monoethylamine, diet-hylamine, monopropylamine, dipropylamine, monobutylamine or dibutylamine will produce the 3-carbamyl 6-bromo-2-ethyl; 3-methylcarbamyl-6-bromo-2-ethyl; 3jdimethylcarbamyl-6ebromo-2-ethyl; 3 ethylcarbamyl-6- bromo-2ethyl; 3-diethylcarbarnyl-6-bromo-2-ethyl; 3- propylcarbamyl-6-brorno-2-ethyl; 3 dipropylcarbamyl-6- brorno-Z-ethyl; 3-butylcarbamyl-6-brorno-2-ethyland 3'- dibutylcarba-myl-6 bromo-2-ethyl derivatives of 7-sulfamyl-3,4-dihydro-l,2,4-benzothiadiazine-1,l-dioxide, respectively.

3-carboxy-6-trifiuorornethyl-Z-methyl derivative by the reaction of 4-amino 6 trifluoromethyl-3-(methylsulfamyD-benzenesulfonamide with glyoxylic acid. Further reaction of this derivative with methanol, ethanol, propanol or isobutanol in the presence of hydrogen chloride results in the formation of the 3-carbornethoxy-6-trifluoromethyl-2-methyl; 3-carbethoxy-6-trifiuoromethyl-2- methyl; 3-carbopropoxy-6-trifiuoromethyl-2-methyl and 3-carbo-iscbutoxy-6-trifiuoromethyl-2methyl derivatives,

respectively. Subsequent reaction of any of these S-car lower-alltyl radical containing from 1 to 4 carbon atoms,

Step A of the method can be carried out conveniently by heating a mixture of two molecular proportions of urea and one molecular proportion of a 5-halo-2,4-disulfamylaniline at a temperature of about 180 C. for a period of about one hour. Upon completion of the reaction, water is added to the reaction mixture which is thereafter heated to effect solution. The aqueous solution is then treated with charcoal and filtered. The filtrate is acidified to precipitate the desired 3-keto-6-halo- 7-sulfamyl 3,4 dihydro 1,2,4 benzothiadiazine-Ll-dioxide as a crystalline solid which is separated by filtration and dried.

Step B of the method is carried out by adding one molecular proportion of an alkali metal hydride, preferably sodium hydride, to a solution of one molecular proportion of a 3-keto-6-halo-7-sulfamyl-3,4-dihydro-1,2,4- benzothiadiazine-1,1-dioxide in dry dimethylformamide. The mixture is stirred and heated to about 70 C. to effect solution. One molecular proportion of an alkyl iodide dissolved in dimethylformamide is thereafter added dropwise and stirring is continued for about two hours at 70 C. When the reaction is complete, the reaction mixture is poured into water and cooled below room temperature to precipitate the desired 2-alkyl-3-keto-6-halo-7-sulfamyl-3,4-dihydro 1,2,4 benzothiadiazine-l,l-dioxide as a crystalline solid which is separated by filtration and dried.

In Step C of the method, a mixture of a 2-alkyl-3- keto-6-halo-7-sulfamyl 3,4 dihydro 1,2,4 benzothiadiazine-l,1-di0xide and an aqueous alkali metal hydroxide solution, preferably sodium hydroxide, is heated at the boiling temperature and under reflux for a period of time to complete the reaction. After treatment with charcoal, the reaction mixture is filtered and the filtrate acidified to obtain the desired 2-alkylsulfamyl-4-sulfamyl-5-haloaniline as a White solid which is separated and dried.

What we desire to particularly point out and distinctly claim as our invention is:

1. 3-carbomethoxy-6-chlore-2-methyl-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1, l-dioxide.

2. 3-carboxy-6chloro-2-methyI-7-sulfamyl-3,4-dihydrol,2,4-benzothiadiazine-1,l-dioxide.

3. B-carbamyl--chloro 2 methyl-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.

4. 6-chloro-3- dimethylcarb amyl) -2-methyl-7-sulfamyl- 3,4-dihydro-l,2,4-benzothiadiazine-l,l-dioxide.

5. 6-bromo-3-carboxy-2-methyl-7-sulfamyl-3,4-dihydro- 1,2,4-benzothiadiazine-1, l-dioxidc.

6. 6-bromo-3-carbomethoxy-2-methyl-7-sulfamyl-3,4-dihydro-l,2,4-benzothiadiazine-1,l-dioxide.

7. 3-carboxy-7-sulfamyl-6-trifluorornethyl 3,4-dihydro- 1,2,4-benzothiadiazine-1,1-dioxide.

8. 3-carbomethoxy-6-chloro-2-ethyl-7 sulfamy1-3,4-dihydro-1,2,4-benzothiadiazine-1,l-dioxide.

9. 6-chloro-2-methyl-3-(methylcarbamyl)-7 sulfamyl- 3,4-dihydro-1,2,4-benzothiadiazine-1,l-dioxide.

10. Compounds selected from the group consisting of .(a) a compound corresponding to the formula X (|JH-llI|I-O-R mNons- 0 S02 and (b) a compound corresponding to the formula t t- H NO S- LR 0 S02 wherein X is a member selected from the group consisting of chlorine, bromine and trifiuoromethyl, and R, R and R" are members selected from the group consisting of hydrogen and lower alkyl.

'11. A compound of the formula e F36 oH-o 0 o R HrNOgS- wherein R is a member selected from the group consisting of hydrogen and lower alkyl.

References Cited in the file of this patent Freeman et al.: Iour. Org. Chem,, volume 16 (1951), page 821.

Wagner et al.: Synthetic Organic Chemistry, pages 480-481 and 568-569 (1953). 

10. COMPOUNDS SELECTED FROM THE GROUP CONSISTING OF (A) A COMPOUND OF CORRESPONDING TO THE FORMULA 